This application is a 371 of RCT/CN 00/00187 filed Jul. 3, 2000, now WO 01/42204 published Aug. 14, 2001.
The invention relates to N-substituted benzyl or phenyl aromatic sulfonamide compounds, namely N-(3,5-bis-disubstituted aminomethyl-4-hydroxy)-benzyl (or phenyl) aromatic sulfonamide compounds, and the physiologically acceptable salts thereof.
Synthesis and antiarrhythmic activities of changrolin (1) have been reported (Liangquan Li, et al., Scientia Sinica, 1979, 7, 723; Weizhou Chen, et al., Acta Pharmaceutica Sinica, 1979, 14, 710). Thereafter, investigations of the chemical structural modifications and the physiological activities have successively been carried out by domestic and foreign scientists (Cunji Sun, et al., Acta Pharmaceutica Sinica, 1981, 16, 564; 1986, 21, 692; Mulan Lin, et al., ibid., 1982, 17, 212; D. M. Stout, et al. J. Med. Chem., 1983, 26, 808; 1984, 27, 1347; 1985, 28, 295; 1989, 32, 1910; R. J. Chorvat, et al., ibid., 1993, 36, 2494). 
Changrolin is an effective antiarrhythmic agent. Ventricular premature beats disappear 2-3 days after oral administration of changrolin to patients suffering from arrhythmia; I.v. injection or instillaton may result in significant reduction or even disappearence of ventricular premature beats and ventricular tachycardia. However, oral administration of changrolin for a period of over one month may cause a reversible pigmentation on the skin of patients, which gradually retrogresses after ceasing the administration. This pigmentation is associated to the subcutaneous oxidation of certain structural moieties in changrolin molecule or to its instability in solution.
It is the purpose of the invention to provide a new class of antiarrhythmic agents which exhibit antiarrhythmic effects superior to those of changrolin and can overcome the
The invention discloses a class of N-substituted benzyl or phenyl aromatic sulfonamide compounds having the general formula of 
Compound 2 or the salt thereof can be obtained by the method shown below: 
Compound 3 can be obtained by the method shown below: 
Alternatively . . . 
Compounds 3 are then converted into the physiologically acceptable salts thereof.
Hereinafter, the embodiments of the present invention are described in detail as follows:
I. For compounds having the general formula of 
wherein
Ar represents phenyl or naphthyl optionally substituted with an alkyl, an alkoxy, a nitro, a halogen or a substituted amino group,
n=0 or 1,
NR2 represents N(CxH2x+1)2, 
xe2x80x83and the like, wherein x=1 or 2, and m=4, 5 or 6, and the preparation process comprises the following steps:
1. Reacting a substituted aromatic sulfonyl chloride with hydroxybenzylamine to thereby form the corresponding aromatic sulfonamide 4;
2. Conducting Mannich reaction of sulfonamide 4 with formaldehyde and a sencondary amine to thereby obtain diamine compound 2;
3. Converting the above obtained diamine compound 2 with inorganic or organic acids into the corresponding salt 5. 
II. For compounds having the general formula of 
wherein
Ar represents phenyl or naphthyl optionally substituted with an alkyl, an alkoxy, a nitro, a halogen or a substituted amino group,
NR2 represents N(CxH2+1)2, 
xe2x80x83and the like, wherein m=4, 5 or 6, and x=1 or 2,
the preparation process comprises the following steps:
1. Conducting a direct condensation between a substituted aromatic sulfonyl chloride and 4-amino-2,6-bis-disubstituted-aminomethylphenol 6 to thereby form sulfonamide 3;
2. Converting sulfonamide 3 with an acid into a physiologically acceptable salt 7.
Compound 6 can be prepared by Mannich reaction of a substituted aminophenol with formaldehyde and a secondary amine: 
Alternatively, it can be prepared by the procedures similar to those for the preparation of 
Namely,
1. Condensing an aromatic sulfonyl chloride with xcfx81-aminophenol to thereby form the corresponding sulfonamide 4 (n=0);
2. Reacting sulfonamide 4 (n=0) with formaldehyde and a secondary amine to thereby form diamine 3;
3. Converting diamine 3 with an acid into salt 7.
By using the above-mentioned methods, compounds having the general formula of 
can be prepared respectively. See Table 1.
Compounds having the general formula of 
are shown in Table 2.
The N-substituted benzyl or phenyl aromatic sulfonamide compoundgs of the invention were used in the preparation of pharmaceuticals for the prophylaxis and treatment of arrhythmia.
The physiologically acceptable hydrochloride salts prepared from the compounds having the general formula of 
according to the present invention have been evaluated for their antiarrhythmic activities by using experimental arrhythmia animal models. The experimental models used and the results obtained are described as follows:
1. An acute myocardial ischemia induced arrhythmia model was obtained by conducting chest opening to expose the heart and deligation of the anterior descending branch of the coronary artery in anesthetized rats (xe2x80x9cMethods in Pharmacological Experimentsxe2x80x9d, Second Edition, p. 1022, People""s Medical Publishing House, Beijing, 1991). By this model, compound B-87823 exhibits activities of significant reduction of ventrical premature beat (effective rate: 77% and inhibits the incidence of ventrical tachycardia up to 73%, while changrolin inhibits the incidence of ventrical premature beats at 50%.
2. In a beiwutine induced rat arrhythmia model (Weizhou Chen, et al., Acta Pharmacologia Sinica, 1983, 4, 247), compound B-87823 shows an ED50 of 2.8 mg/kg for prophylatic administration with a prophylatic index of 37 and a therapeutic dose of 5.9xc2x10.5 mg/kg for therapeutic administration with a therapeutic index of 18; while changrolin has its ED50 of 3 mg/kg.
3. In an ouabain induced guinea pig arrhythmia model (Weizhou Chen, et al., Acta, Pharmacologia Sinica, 1983, 4, 247), both of compound B-87823 and changrolin can significantly increase the amount of ouabain used for inducing ventrical premature beats, ventricular tachycardia and ventricular fibrillation.
4. Compound B-87823 also shows significant inhibition on arrhythmia induced by reperfusion in the isolated guinea pig heart (Yueli Dong, et al., Acta Pharmaceutica Sinica, 1995, 30, 577).
5. Compound B-87823 exhibits an activity against the beiwutine-induced heterotopia rhythm of isolated guinea pig papillary muscles (Hongzhuan Chen, et al., Acta Universitatis Medicinalis Secondae Shanghai, 1989, 9, 105) and gives a negative response to the Ames test. The pharmacological effects of individual compounds of the invention are shown in Table 3.
6. In a fast response action potential model of guinea pig papillary muscle cells (xe2x80x9cMethods in Pharmacological Experimentsxe2x80x9d, Second Edition, p. 563, The People""s Hygiene Publisher, Beijing, 1991), compound B-87823 was observed to be capable of reducing the amplitude of the action potential and the maximum upstroke velocity of the action potential, extending the action potential duration at 90% repolarization and the effective refractory period (see Table 4).
7. In a slow response action potential model of rabbit sinoatrial nodal dominant pacemaker cells (xe2x80x9cMethods in Pharmacological Experimentsxe2x80x9d, Second Edition, p. 563, People""s Medical Publishing House, Beijing, 1991), compound B-87823 was found to be capable of reducing the maximum upstroke velocity of the action potential and the slope of phase 4 depolarization, and decreasing the amplitude of the action potential (see Table 5).
8. In a model of Harris two-stage coronary artery ligation-induced delayed developing arrhythmia in conscious dog (Harris, A. S. Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation Res. 1950; 1:1318-1328), it was observed that oral administration of compound B-87823 could significantly reduce the nodal and ventricular premature beats as well as the episodic ventricular tachycardia (see Table 6).
9. In an ischemia reperfusion model of the isolated guinea pig heart (Woodward, B. A model of ventricular fibrillation in the isolated rat heart. J Pharmac Meth. 1981; 6:219-231), compound B-87823 was found to be capable of significantly inhibiting the ventricular fibrillation caused by the reperfusion injury (see Table 7).
Table 4 Electro-physiological effects of B-87823 on the fast response action potential of guinea pig papillary muscle cells ({overscore (X)}xc2x1SD, n=6, *P less than 0.05, **P less than 0.01)
Table 5 Electro-physiological effects of B-87823 on the slow response action potential of rabbit sinoatrial nodal dominant pacemaker cells ({overscore (X)}xc2x1SD, n=5, *P less than 0.05, **P less than 0.01)
Table 6 Effects of oral administration of B-87823 on Harris two-stage coronary artery ligation-induced delayed arrhythmia in conscious dog ({overscore (X)}xc2x1SD, n=6, **P less than 0.01)
Table 7 Effect of B-87823 on ventriculur fibrillation induced by ischemia reperfusion injury in isolated guinea pig heart
The prophylatic indexes and therapeutic indexes shown in Table 3 were obtained by the following procedure: performing an acute toxicity test in rats to obtain the medium lethal dose (LD50), then conducting prophylatic tests by using the rat aconitine-induced arrhythmia model in rat to obtain medium effective dose (ED50), obtaining the effective dose (ED) by therapeutic tests, calculating the prophylatic indexes as a ratio of LD50:ED50 and the therapeutic indexes as a ratio of LD50:ED, which were used to evaluate these compounds for their antiarrhythmic activities.
It can be seen from Table 3 that the hydrochloride of compound B-87823 exhibits the highest prophylatic and therapeutic indexes.